Enhancing the Oral Absorption of Kinase Inhibitors Using Lipophilic Salts and Lipid-Based Formulations

Hywel D. Williams, Leigh Ford, Sifei Han, Kristian J. Tangso, Shea Lim, David M. Shackleford, David T. Vodak, Hassan Benameur, Colin W. Pouton, Peter J. Scammells, Christopher J.H. Porter

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The absolute bioavailability of many small molecule kinase inhibitors (smKIs) is low. The reasons for low bioavailability are multifaceted and include constraints due to first pass metabolism and poor absorption. For smKIs where absorption limits oral bioavailability, low aqueous solubility and high lipophilicity, often in combination with high-dose requirements have been implicated in low and variable absorption, food-effects, and absorption-related drug-drug interactions. The current study has evaluated whether preparation of smKIs as lipophilic salts/ionic liquids in combination with coadministration with lipid-based formulations is able to enhance absorption for examples of this compound class. Lipophilic (docusate) salt forms of erlotinib, gefitinib, ceritinib, and cabozantinib (as example smKIs demonstrating low aqueous solubility and high lipophilicity) were prepared and isolated as workable powder solids. In each case, the lipophilic salt exhibited high and significantly enhanced solubility in lipidic excipients (>100 mg/g) when compared to the free base or commercial salt form. Isolation as the lipophilic salt facilitated smKI loading in model lipid-based formulations at high concentration, increased in vitro solubilization at gastric and intestinal pH and in some cases increased oral absorption (∼2-fold for cabozantinib formulations in rats). Application of a lipophilic salt approach can therefore facilitate the use of lipid-based formulations for examples of the smKI compound class where low solubility limits absorption and is a risk factor for increased variability due to food-effects.

Original languageEnglish
Pages (from-to)5678−5696
Number of pages19
JournalMolecular Pharmaceutics
Volume15
Issue number12
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Biopharmaceutical Classification System
  • drug absorption
  • drug delivery
  • ionic liquids
  • kinase inhibitors
  • lipid-based formulations
  • lipophilic salts
  • poorly water-soluble drug
  • SEDDS

Cite this

Williams, Hywel D. ; Ford, Leigh ; Han, Sifei ; Tangso, Kristian J. ; Lim, Shea ; Shackleford, David M. ; Vodak, David T. ; Benameur, Hassan ; Pouton, Colin W. ; Scammells, Peter J. ; Porter, Christopher J.H. / Enhancing the Oral Absorption of Kinase Inhibitors Using Lipophilic Salts and Lipid-Based Formulations. In: Molecular Pharmaceutics. 2018 ; Vol. 15, No. 12. pp. 5678−5696.
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Enhancing the Oral Absorption of Kinase Inhibitors Using Lipophilic Salts and Lipid-Based Formulations. / Williams, Hywel D.; Ford, Leigh; Han, Sifei; Tangso, Kristian J.; Lim, Shea; Shackleford, David M.; Vodak, David T.; Benameur, Hassan; Pouton, Colin W.; Scammells, Peter J.; Porter, Christopher J.H.

In: Molecular Pharmaceutics, Vol. 15, No. 12, 01.01.2018, p. 5678−5696.

Research output: Contribution to journalArticleResearchpeer-review

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